1. Field of the Invention
The present invention relates generally to the field of biodegradable microparticles for the controlled release of biologically active agents therefrom. In addition, the present invention relates to a process for preparing polyester microparticles containing peptides which remain chemically stable, physically stable, and biologically active.
2. Background of the Invention
A variety of microencapsulation techniques have been used for years by the pharmaceutical industry to separate incompatible chemical entities, to convert liquids to free-flowing powder, to improve the dissolution rates and bioavailabilities of drugs, to protect the compounds from decomposition, and to mask unfavorable odor or taste. Another area to benefit from microencapsulation technology is the development of controlled-release formulations. Numerous carriers and encapsulation techniques have been evaluated and characterized. As a result, microcapsules with sustained-release properties have been successfully developed. However, most drugs that have been used in these microparticles have been relatively water-insoluble.
While water-insoluble compounds have inherent sustained-release properties when incorporated in a polymer matrix, and are relatively easy to encapsulate, preparation of sustained-release microcapsules of water-soluble pharmaceuticals poses a great challenge to pharmaceutical scientists. It is not surprising, therefore, that the literature provides little information on the microencapsulation of water-soluble drugs.
Peptide drugs are attracting increasing interest as their role in physiopathology becomes better understood, and because of progress in biotechnology and in conventional chemical synthesis. The development of DNA-recombination techniques has made these compounds available on a larger scale than in the past. However, peptides are generally characterized by a short biological half-life. This and other factors have led to the development of many new drug delivery systems, including the use of microparticles for the safe and controlled administration of peptides.
Microparticles are spherical polymeric particles ranging in size from greater than one micron up to 2000 microns. Microparticles include microcapsules in which the biological agent is uniformly confined within a cavity, and microspheres in which the agent is dispersed throughout the microparticle. Many processes can be used for the preparation of microparticles, including solvent evaporation, organic phase separation, interfacial polymerization, emulsion polymerization, and spray drying. However, only a few methods are acceptable for preparing peptide microparticles. The physicochemical properties of many peptides make their formulation difficult, and inactivation is possible during their incorporation into microparticles.
Numerous polymers have been used as matrices for microparticles, including polysaccharides, polyesters and nonbiodegradable synthetic polymers. Most methods for microencapsulation of peptides employ polyesters, especially poly(D,L-lactide-co-glycolide). The polyesters are desireable for this purpose because they are biodegradable or bioerodible, readily available, easily processed and non-toxic.
Microspheres of lactic and glycolic acids may be obtained conveniently by a solvent evaporation process which is, in spite of some limitations, compatible with the handling of numerous peptides. However, a major obstacle to the particulate formulation of peptides is the high water solubility of those molecules. The typical processes for microencapsulation are based on the affinity of the compound for the polymer or for the lipophilic phase of an emulsion. As a result, drug loadings for peptides have typically been less than 10% with the solvent evaporation processes used in the past.
Prior art efforts to overcome these problems have thus far included the use of a double emulsion technique, and of a phase separation process induced by the addition of a silicone oil. However, there has remained a need for methods for the preparation of biodegradable microparticles incorporating peptides which are stable and active, and which pay out at desired rates over time.